Cancer Letters

Cancer Letters

Volume 211, Issue 1, 28 July 2004, Pages 39-46
Cancer Letters

Inhibition of cyclooxygenase-2 activity in head and neck cancer cells by genistein

https://doi.org/10.1016/j.canlet.2004.03.043Get rights and content

Abstract

Genistein, rich in soybean, has been reported to have anti-cancer activity on several cancers. However, the molecular mechanism of its anti-cancer activity still remains unclear. We investigated the effect of genistein on a human oral squamous carcinoma line (SCC-25), and demonstrated that genistein inhibited SCC-25 cell growth via G2/M phase arrest. We observed a significant decrease of proliferating cell nuclear antigen expression in these cells after treatment, but no significant change in the number of apoptotic cells, indicating that the major action of genistein is inhibition of cancer cell proliferation. We also observed a high level of prostaglandin E2 (PGE2) in these cells and PGE2 synthesis in SCC-25 cells was significantly suppressed by genistein. We demonstrated that genistein directly inhibited cycloxygenase-2 (COX-2) activity, an inducible enzyme that converts arachidonic acid to prostaglandins, similar to the action of celecoxib, a selective COX-2 inhibitor. However, the anticancer activity of genistein was much weaker than that of indomethacin (non-selective COX inhibitor), celecoxib and baicalein (flavonoid isolated from Scutellaria baicalensis). These results suggested that genistein might be useful as a chemopreventive agent rather than a chemotherapeutic agent.

Introduction

According to the report of the International Agency for Research on Cancer, approximately 170,000 men and 97,000 women worldwide have cancers of the oral cavity, and the most prevalent type of cancer is squamous cell carcinoma. In 2000, over 20,000 cases and nearly 5,000 deaths were reported in North America, including the United States and Canada [1]. If oral cancer is treated in the early stage of tumor progression, the chance of cure is high. Unfortunately, most patients with this type of cancer have advanced disease at the time of diagnosis. Therefore, much research is currently devoted to chemotherapy and chemoprevention in order to treat or prevent oral cancers at an early stage.

The arachidonic acid pathway is of particular importance to the etiology of head and neck squamous cell carcinoma (HNSCC). Arachidonic acid, a 20-carbon polyunsaturated fatty acid, is a phospholipid component of cell membranes. Two key enzymes in arachidonic acid metabolism are cyclooxygenase-1 (COX-1) and -2 (COX-2); the former is the constitutive isoform while the latter is inducible. An overproduction of COX-2 enzyme that catalyzes arachidonic acid metabolism to form prostaglandin E2 (PGE2) facilitates proliferation of neoplastic cells [2]. Patients with HNSCC have higher serum levels of PGE2 compared to healthy volunteers [3]. It has been shown that PGE2 was the predominant arachidonic acid metabolite in HNSCC [2]. Therefore, it is important to search for agents that inhibit the arachidonic acid pathway for the chemotherapeutic or chemopreventive treatment of HNSCC. Such work has lead to the discovery of current drugs including indomethacin that targets COX-1 and COX-2, and celecoxib that specifically targets the COX-2 enzyme.

Genistein, one of the isoflavones rich in soybean and some forage plants, has been implied to decrease both the incidence and mortality in various cancers, including breast and prostate cancers [4], [5]. In vitro studies demonstrated that genistein inhibits HNSCC cancer cell growth [6], [7] and reduces PGE2 levels in mouse macrophages [8]. To further explore the mechanism of its anticancer activity, we investigated its effects on a human oral squamous carcinoma cell line, SCC-25. Our study revealed that genistein exhibited a significant inhibition on the growth of SCC-25 cells in parallel with the reduction of PCNA expression and PGE2 levels. These results suggested that genistein is a potential agent for cancer prevention.

Section snippets

Cell culture

SCC-25 cell line (American Type Culture Collection, Manassas, VA) was derived from tongue squamous cell carcinoma. The cells were incubated at 37 °C with a 5% CO2 atmosphere in a 50:50 mixture of DMEM and F12 containing 1% antibiotic/antimycotic, and 10% Fetal Bovine Serum.

Cell growth inhibition assay

Growth inhibition of genistein was determined by an MTT (3, 4, 5-dimethylthiazol-2, 5-diphenyltetrazolium bromide; Sigma, St. Louis, MO) assay to measure viable cells. Approximately 5×103 cells were seeded onto each well of a

Genistein inhibits cell growth

We investigated the anti-cancer activity of genistein and compared it with indomethacin (a nonselective COX inhibitor), celecoxib (a COX-2 specific inhibitor), and baicalein (an isoflavone isolated from an herbal medicine, Scutellaria baicalensis). Our results show that all of four agents were capable of inhibiting the growth of human oral squamous carcinoma cells (SCC-25) (Fig. 1). Among these four agents, celecoxib exerted the strongest inhibitory effect on SCC-25 cells with a 50% inhibition

Discussion

Extensive work on the cancer-treating potential of genistein has been reported since a workshop at the National Cancer Institute on the observed anti-carcinogenic properties of soybeans in 1990 [13]. Subsequent epidemiological studies conducted on the effects of soy intake on populations revealed that in China and Japan, where soy consumption is high, incidences of breast, colon, and prostate cancers were lower than those in Western nations [14], [15]. There are also much lower occurrences of

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